Autism Spectrum Disorder (ASD) is characterized by pervasive socio-emotional and cognitive deficits even in children with high intellectual function. Its neuropathophysiology involves executive dysfunction mediated by prefrontal cortex but is not well-understood, due to high phenotypic heterogeneity and comorbidity with attention and anxiety disorders and a lack of resolution in affected component processes of executive function. We postulate that symptom expression varies among ASD children due to the influence of traits that characterize comorbid disorders (impulsivity, anxiety). Examining differences in functional brain organization of executive control due to anxiety and impulsivity with sensitive fMRI probes will elucidate phenotypic heterogeneity in ASD children. Guided by developmental neuroanatomical models, we will examine multiple top-down control processes and bottom-up perceptual processes that function in adaptive balance to serve goal-directed behavior. We will test the hypothesis that specific prefrontal-striato- limbic circuits, which mediate that adaptive balance, are atypical in ASD. We will manipulate component operations of top-down (voluntary, involuntary) and bottom-up (attention bias to salience) processing in 9-12 year-old high-functioning ASD children and age, Verbal IQ, and gender matched controls. Group differences and individual variation by anxiety, impulsivity, and symptom severity will be examined with confirmatory (hypothesis-driven) and exploratory (data-driven) analysis of functional networks and underlying white-matter microstructure. Aim I examines whether voluntary and involuntary control of attention is modulated by stimulus saliency (i.e., perceptual novelty, emotion) atypically in ASD. Exp 1 will examine incidental (involuntary) and intentional (voluntary) encoding of salient (novel/infrequent vs. familiar/repeated) distracters in the context of an ongoing task. Exp 2 will examine exogenous (involuntary) and endogenous (voluntary) attentional bias to salient faces (angry vs. neutral) in the Dot-probe task. Aim 2 examines whether voluntary and involuntary control of responses is modulated by stimulus domain (social-emotional or non- social) atypically in ASD. Exp 3 will examine voluntary response control (response inhibition and interference suppression) and involuntary context adaptation during a Flanker task with symbolic (non-social) stimuli. Exp 4 will examine voluntary response control during conflict varying in socio-emotional significance in a Stroop-like task. Aim 3 will examine whether intrinsic resting-state connectivity is atypical in ASD. Current research shows parallel functional organization during behavioral and resting states. We will search for resting-state correlates of component operations of executive control pooled by voluntary and involuntary conditions and domains (non-social, socio-emotional) from Exps 1-4 and determine whether they are atypical in ASD and vary by anxiety, impulsivity, and symptom severity. New knowledge from this proposal will refine models of ASD neuropathophysiology and provide targets for pharmacological and behavioral intervention. PUBLIC HEALTH RELEVANCE: This project aims to elucidate individual differences in functional brain organization of higher cognition in 9-12 year old children with Autism Spectrum Disorders with normal intellectual function. It will use brain imaging to examine whether functional brain organization of executive function varies by anxiety and impulsivity that are reflected in symptoms of the disorder. Knowledge gained from proposed studies will refine clinical characterization and reveal new targets for pharmacological and behavioral treatment for Autism Spectrum Disorders.